DESCRIPTION (provided by aplicant): Amongst the greatest risks to human public health is the possibility of large outbreaks of viruses or anti biotic resistant bacteria (natural or engineered) occurring with speeds that would not allow the development and timely administration of prophylactic vaccines. A potential means of rapidly protecting at-risk populations from such outbreaks might be to activate innate immunity so as to provide a window of non-specific containment thus allowing time for adaptive immunity to develop to the challenging pathogen. Limited efforts at developing this approach have had moderate success and remain under investigation. These efforts have focused exclusively on innate immune activators such as lipopolysacharride and bacterial DNA (DNA with unmethylated CpG) that primarily activate immune cells. However, as most pathogens first colonize their hosts via the epithelial cells that line mucosal surfaces, we hypothesize that activating anti-microbial gene expression in epithelial cells might provide a substantially greater level of protection against most pathogenic challenges. Our on-going studies on gut-bacterial interactions have revealed that bacterial flagellin is a dominant innate immune activator of epithelial cells and thus might be an ideal agonist to transiently boost mucosal host defense. Thus, the overall goal of this application, submitted in response the NIH announcement of ARRA funds for Competitive Revision Applications (NOT-OD-09-058), is to leverage our ongoing studies on flagellin induced gut epithelial chemokine secretion to begin to develop a new paradigm of protection against pandemic infection. PUBLIC HEALTH RELEVANCE: The overall goal of this application is to leverage our ongoing studies on flagellin-induced gut epithelial chemokine secretion to begin to develop a new paradigm of protection against pandemic infection.